Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

CHD Exome+ Consortium; CARDIoGRAM Exome Consortium; Global Lipids Genetics Consortium

doi:10.1126/science.aad3517

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

CHD Exome+ Consortium, CARDIoGRAM Exome Consortium, Global Lipids Genetics Consortium

Department of Clinical Medicine

278 Citations (Scopus)

Abstract

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

Original language	English
Journal	Science (New York, N.Y.)
Volume	351
Issue number	6278
Pages (from-to)	1166-71
Number of pages	6
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.aad3517
Publication status	Published - 11 Mar 2016

Keywords

Aged
Amino Acid Substitution
Animals
Cholesterol, HDL
Coronary Disease
DNA Mutational Analysis
Female
Genetic Variation
Heterozygote
Homozygote
Humans
Leucine
Male
Mice
Middle Aged
Proline
Protein Processing, Post-Translational
Risk
Scavenger Receptors, Class B
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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title = "Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease",

abstract = "Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).",

keywords = "Aged, Amino Acid Substitution, Animals, Cholesterol, HDL, Coronary Disease, DNA Mutational Analysis, Female, Genetic Variation, Heterozygote, Homozygote, Humans, Leucine, Male, Mice, Middle Aged, Proline, Protein Processing, Post-Translational, Risk, Scavenger Receptors, Class B, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

author = "Paolo Zanoni and Khetarpal, {Sumeet A} and Larach, {Daniel B} and Hancock-Cerutti, {William F} and Millar, {John S} and Marina Cuchel and Stephanie DerOhannessian and Anatol Kontush and Praveen Surendran and Danish Saleheen and Stella Trompet and Jukema, {J Wouter} and {de Craen}, {Anton Jm} and Panos Deloukas and Naveed Sattar and Ian Ford and Chris Packard and Majumder, {Abdullah al Shafi} and Alam, {Dewan S} and {Di Angelantonio}, Emanuele and Goncalo Abecasis and Rajiv Chowdhury and Jeanette Erdmann and Nordestgaard, {B{\o}rge G} and Nielsen, {Sune F} and Anne Tybj{\ae}rg-Hansen and Schmidt, {Ruth Frikke} and Kari Kuulasmaa and Liu, {Dajiang J} and Markus Perola and Stefan Blankenberg and Veikko Salomaa and Satu M{\"a}nnist{\"o} and Philippe Amouyel and Dominique Arveiler and Jean Ferri{\`e}res and Martina M{\"u}ller-Nurasyid and Ferrario, {Marco M} and Frank Kee and Willer, {Cristen J} and Samani, {Nilesh J} and Heribert Schunkert and Butterworth, {Adam S} and Howson, {Joanna M. M.} and Peloso, {Gina M} and Stitziel, {Nathan O} and John Danesh and Sekar Kathiresan and Rader, {Daniel J} and {CHD Exome+ Consortium} and {CARDIoGRAM Exome Consortium} and {Global Lipids Genetics Consortium}",

note = "Copyright {\textcopyright} 2016, American Association for the Advancement of Science.",

year = "2016",

month = mar,

day = "11",

doi = "10.1126/science.aad3517",

language = "English",

volume = "351",

pages = "1166--71",

journal = "Science (New York, N.Y.)",

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TY - JOUR

T1 - Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

AU - Zanoni, Paolo

AU - Khetarpal, Sumeet A

AU - Larach, Daniel B

AU - Hancock-Cerutti, William F

AU - Millar, John S

AU - Cuchel, Marina

AU - DerOhannessian, Stephanie

AU - Kontush, Anatol

AU - Surendran, Praveen

AU - Saleheen, Danish

AU - Trompet, Stella

AU - Jukema, J Wouter

AU - de Craen, Anton Jm

AU - Deloukas, Panos

AU - Sattar, Naveed

AU - Ford, Ian

AU - Packard, Chris

AU - Majumder, Abdullah al Shafi

AU - Alam, Dewan S

AU - Di Angelantonio, Emanuele

AU - Abecasis, Goncalo

AU - Chowdhury, Rajiv

AU - Erdmann, Jeanette

AU - Nordestgaard, Børge G

AU - Nielsen, Sune F

AU - Tybjærg-Hansen, Anne

AU - Schmidt, Ruth Frikke

AU - Kuulasmaa, Kari

AU - Liu, Dajiang J

AU - Perola, Markus

AU - Blankenberg, Stefan

AU - Salomaa, Veikko

AU - Männistö, Satu

AU - Amouyel, Philippe

AU - Arveiler, Dominique

AU - Ferrières, Jean

AU - Müller-Nurasyid, Martina

AU - Ferrario, Marco M

AU - Kee, Frank

AU - Willer, Cristen J

AU - Samani, Nilesh J

AU - Schunkert, Heribert

AU - Butterworth, Adam S

AU - Howson, Joanna M. M.

AU - Peloso, Gina M

AU - Stitziel, Nathan O

AU - Danesh, John

AU - Kathiresan, Sekar

AU - Rader, Daniel J

AU - CHD Exome+ Consortium

AU - CARDIoGRAM Exome Consortium

AU - Global Lipids Genetics Consortium

PY - 2016/3/11

Y1 - 2016/3/11

N2 - Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

AB - Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

KW - Aged

KW - Amino Acid Substitution

KW - Animals

KW - Cholesterol, HDL

KW - Coronary Disease

KW - DNA Mutational Analysis

KW - Female

KW - Genetic Variation

KW - Heterozygote

KW - Homozygote

KW - Humans

KW - Leucine

KW - Male

KW - Mice

KW - Middle Aged

KW - Proline

KW - Protein Processing, Post-Translational

KW - Risk

KW - Scavenger Receptors, Class B

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1126/science.aad3517

DO - 10.1126/science.aad3517

M3 - Journal article

C2 - 26965621

SN - 0036-8075

VL - 351

SP - 1166

EP - 1171

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6278

ER -

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

Abstract

Keywords

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